Delivery of sumatriptan, frovatriptan or naratriptan through an inhalation route

ABSTRACT

The present invention relates to the delivery of anti-migraine compounds through an inhalation route. Specifically, it relates to aerosols containing sumatriptan, frovatriptan, or naratriptan that are used in inhalation therapy. In a method aspect of the present invention, one of sumatriptan, frovatriptan, or naratriptan is administered to a patient through an inhalation route. The method comprises: a) heating a composition, comprising sumatriptan, frovatriptan, or naratriptan, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol with less than 5% of the drug degradation products. In a kit aspect of the present invention, a kit for delivering sumatriptan, frovatriptan, or naratriptan through an inhalation route is provided which comprises: a) a thin coating of a sumatriptan, frovatriptan, or naratriptan composition; and, b) a device for dispending said thin coating as a condensation aerosol

[0001] This application is a continuation of U.S. patent applicationSer. No. 10/155,705, entitled “Delivery of Sumatriptan, Frovatriptan orNaratriptan Through an Inhalation Route,” filed May 22, 2002, Hale,Rabinowitz, Solas, and Zaffaroni; which claims priority to U.S.provisional application Ser. No. 60/294,203 entitled “Thermal VaporDelivery of Drugs,” filed May 24, 2001, Rabinowitz and Zaffaroni, and toU.S. provisional application Ser. No. 60/317,479 entitled “Aerosol DrugDelivery,” filed Sep. 5, 2001, Rabinowitz and Zaffaroni, the entiredisclosures of which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to the delivery of anti-migrainecompounds through an inhalation route. Specifically, it relates toaerosols containing sumatriptan, frovatriptan, or naratriptan that areused in inhalation therapy.

[0003] 1. Background of the Invention

[0004] There are a number of compositions currently marketed for thetreatment of migraine headaches. The compositions contain at least oneactive ingredient that provides for observed therapeutic effects. Amongthe active ingredients given in such anti-migraine compositions aresumatriptan, frovatriptan, and naratriptan.

[0005] It is desirable to provide a new route of administration forsumatriptan, frovatriptan, and naratriptan that rapidly produces peakplasma concentrations of the compounds. The provision of such a route isan object of the present invention.

[0006] 2. Summary of the Invention

[0007] The present invention relates to the delivery of anti-migrainecompounds through an inhalation route. Specifically, it relates toaerosols containing sumatriptan, frovatriptan, or naratriptan that areused in inhalation therapy.

[0008] In a composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight ofsumatriptan, frovatriptan, or naratriptan. Preferably, the particlescomprise at least 10 percent by weight of sumatriptan, frovatriptan, ornaratriptan. More preferably, the particles comprise at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or99.97 percent by weight of sumatriptan, frovatriptan, or naratriptan.

[0009] Typically, the aerosol has a mass of at least 10 pg. Preferably,the aerosol has a mass of at least 100 μg. More preferably, the aerosolhas a mass of at least 200 μg.

[0010] Typically, the particles comprise less than 10 percent by weightof sumatriptan, frovatriptan, or naratriptan degradation products.Preferably, the particles comprise less than 5 percent by weight ofsumatriptan, frovatriptan, or naratriptan degradation products. Morepreferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03percent by weight of sumatriptan, frovatriptan, or naratriptan.

[0011] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0012] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0013] Typically, where the aerosol comprises sumatriptan, the aerosolhas an inhalable aerosol drug mass density of between 5 mg/L and 40mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 10 mg/L and 35 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 15 mg/L and 30 mg/L.

[0014] Typically, where the aerosol comprises frovatriptan, the aerosolhas an inhalable aerosol drug mass density of between 0.5 mg/L and 4mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 1 mg/L and 3.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 1.5 mg/L and 3.0 mg/L.

[0015] Typically, where the aerosol comprises naratriptan, the aerosolhas an inhalable aerosol drug mass density of between 0.2 mg/L and 2mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 0.3 mg/L and 1.75 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.4 mg/L and 1.5 mg/L.

[0016] Typically, the aerosol has an inhalable aerosol particle densitygreater than 10⁶ particles/mL. Preferably, the aerosol has an inhalableaerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

[0017] Typically, the aerosol particles have a mass median aerodynamicdiameter of less than 5 microns. Preferably, the particles have a massmedian aerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

[0018] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.2.

[0019] Typically, the aerosol is formed by heating a compositioncontaining sumatriptan, frovatriptan, or naratriptan to form a vapor andsubsequently allowing the vapor to condense into an aerosol.

[0020] In another composition aspect of the present invention, a doseform of an antimigraine compound is provided for the treatment ofmigraine, wherein the dose form comprises less than the typical oraldose of the antimigraine compound.

[0021] Typically, where the antimigraine compound is sumitriptan, thedose form comprises less than 20 mg of sumitriptan. Preferably, the doseform comprises less than 15 mg of sumitriptan. More preferably, the doseform comprises less than 10 mg or 5 mg of sumitriptan.

[0022] Typically, where the antimigraine compound is frovatriptan, thedose form comprises less than 2 mg of frovatriptan. Preferably, the doseform comprises less than 1.75 mg of frovatriptan. More preferably, thedose form comprises less than 1.5 mg, 1.25 mg or 1 mg of frovatriptan.

[0023] Typically, where the antimigraine compound is naratriptan, thedose form comprises less than 0.8 mg of naratriptan. Preferably, thedose form comprises less than 0.6 mg of naratriptan. More preferably,the dose for comprises less than 0.4 mg of naratriptan.

[0024] Typically, the dose form further comprises less than 90 percentby weight of water. Preferably, the dose form further comprises lessthan 80 percent by weight of water. More preferably, the dose formfurther comprises less than 70 percent, 60 percent, 50 percent, 40percent, 30 percent, 20 percent, or 10 percent by weight of water.

[0025] Typically, the dose form further comprises less than 90 percentby weight of a pharmaceutically acceptable excipient. Preferably, thedose form further comprises less than 80 percent by weight of apharmaceutically acceptable excipient. More preferably, the dose formfurther comprises less than 70 percent, 60 percent, 50 percent, 40percent, 30 percent, 20 percent, or 10 percent by weight of apharmaceutically acceptable excipient.

[0026] In a method aspect of the present invention, one of sumatriptan,frovatriptan, or naratriptan is delivered to a mammal through aninhalation route. The method comprises: a) heating a composition,wherein the composition comprises at least 5 percent by weight ofsumatriptan, frovatriptan, or naratriptan, to form a vapor; and, b)allowing the vapor to cool, thereby forming a condensation aerosolcomprising particles, which is inhaled by the mammal. Preferably, thecomposition that is heated comprises at least 10 percent by weight ofsumatriptan, frovatriptan, or naratriptan. More preferably, thecomposition comprises at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of sumatriptan, frovatriptan, or naratriptan.

[0027] Typically, the particles comprise at least 5 percent by weight ofsumatriptan, frovatriptan, or naratriptan. Preferably, the particlescomprise at least 10 percent by weight of sumatriptan, frovatriptan, ornaratriptan. More preferably, the particles comprise at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of sumatriptan, frovatriptan, ornaratriptan.

[0028] Typically, the aerosol has a mass of at least 10 g. Preferably,the aerosol has a mass of at least 100 μg. More preferably, the aerosolhas a mass of at least 200 μg.

[0029] Typically, the particles comprise less than 10 percent by weightof sumatriptan, frovatriptan, or naratriptan degradation products.Preferably, the particles comprise less than 5 percent by weight ofsumatriptan, frovatriptan, or naratriptan degradation products. Morepreferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent byweight of sumatriptan, frovatriptan, or naratriptan degradationproducts.

[0030] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0031] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0032] Typically, the particles of the delivered condensation aerosolhave a mass median aerodynamic diameter of less than 5 microns.Preferably, the particles have a mass median aerodynamic diameter ofless than 3 microns. More preferably, the particles have a mass medianaerodynamic diameter of less than 2 or 1 micron(s).

[0033] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.2.

[0034] Typically, where the aerosol comprises sumatriptan, the deliveredaerosol has an inhalable aerosol drug mass density of between 5 mg/L and40 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 10 mg/L and 35 mg/L. More preferably, the aerosol hasan inhalable aerosol drug mass density of between 15 mg/L and 30 mg/L.

[0035] Typically, where the aerosol comprises frovatriptan, thedelivered aerosol has an inhalable aerosol drug mass density of between0.5 mg/L and 4 mg/L. Preferably, the aerosol has an inhalable aerosoldrug mass density of between 1 mg/L and 3.5 mg/L. More preferably, theaerosol has an inhalable aerosol drug mass density of between 1.5 mg/Land 3.0 mg/L.

[0036] Typically, where the aerosol comprises naratriptan, the deliveredaerosol has an inhalable aerosol drug mass density of between 0.2 mg/Land 2 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 0.3 mg/L and 1.75 mg/L. More preferably, the aerosolhas an inhalable aerosol drug mass density of between 0.4 mg/L and 1.5mg/L.

[0037] Typically, the delivered aerosol has an inhalable aerosolparticle density greater than 10⁶ particles/mL. Preferably, the aerosolhas an inhalable aerosol particle density greater than 10⁷ particles/mLor 10⁸ particles/mL.

[0038] Typically, the rate of inhalable aerosol particle formation ofthe delivered condensation aerosol is greater than 10⁸ particles persecond. Preferably, the aerosol is formed at a rate greater than 10⁹inhalable particles per second. More preferably, the aerosol is formedat a rate greater than 10¹⁰ inhalable particles per second.

[0039] Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

[0040] Typically, where the condensation aerosol comprises sumatriptan,between 5 mg and 40 mg of sumatriptan are delivered to the mammal in asingle inspiration. Preferably, between 10 mg and 35 mg of sumatriptanare delivered to the mammal in a single inspiration. More preferably,between 15 mg and 30 mg of sumatriptan are delivered in a singleinspiration.

[0041] Typically, where the condensation aerosol comprises frovatriptan,between 0.5 mg and 4 mg of frovatriptan are delivered to the mammal in asingle inspiration. Preferably, between 1 mg and 3.5 mg of frovatriptanare delivered to the mammal in a single inspiration. More preferably,between 1.5 mg and 3.0 mg of frovatriptan are delivered in a singleinspiration.

[0042] Typically, where the condensation aerosol comprises naratriptan,between 0.2 mg and 2 mg of naratriptan are delivered to the mammal in asingle inspiration. Preferably, between 0.3 mg and 1.75 mg ofnaratriptan are delivered to the mammal in a single inspiration. Morepreferably, between 0.4 mg and 1.5 mg of naratriptan are delivered in asingle inspiration.

[0043] Typically, the delivered condensation aerosol results in a peakplasma concentration of sumatriptan, frovatriptan, or naratriptan in themammal in less than 1 h. Preferably, the peak plasma concentration isreached in less than 0.5 h. More preferably, the peak plasmaconcentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or0.005 h (arterial measurement).

[0044] Typically, where the condensation aerosol comprises sumatriptan,less than 20 mg of sumitriptan is inhaled by the mammal in any 2 hourperiod. Preferably, less than 15 mg of sumitriptan is inhaled by themammal in any 2 hour period. More preferably, less than 10 mg or 5 mg ofsumitriptan is inhaled by the mammal in any 2 hour period.

[0045] Typically, where the condensation aerosol comprises frovatriptan,less than 2 mg of frovatriptan is inhaled by the mammal in any 2 hourperiod. Preferably, less than 1.75 mg of frovatriptan is inhaled by themammal in any 2 hour period. More preferably, less than 1.5 mg offrovatriptan is inhaled by the mammal in any 2 hour period.

[0046] Typically, where the condensation aerosol comprises naratriptan,less than 0.8 mg of naratriptan is inhaled by the mammal in any 2 hourperiod. Preferably, less than 0.6 mg of naratriptan is inhaled by themammal in any 2 hour period. More preferably, less than 0.4 mg ofnaratriptan is inhaled by the mammal in any 2 hour period.

[0047] In another method aspect of the present invention, a method oftreating migraine is provided which comprises administering a dose of anantimigraine compound to a mammal that is less than the typical oraldose.

[0048] Typically, where the antimigraine compound is sumatriptan, lessthan 20 mg of sumitriptan is administered to the mammal in any 2 hourperiod. Preferably, less than 15 mg of sumitriptan is administered tothe mammal in any 2 hour period. More preferably, less than 10 mg or 5mg of sumitriptan is administered to the mammal in any 2 hour period.

[0049] Typically, where the antimigraine compound is frovatriptan, lessthan 2 mg of frovatriptan is administered to the mammal in any 2 hourperiod. Preferably, less than 1.75 mg of frovatriptan is administered tothe mammal in any 2 hour period. More preferably, less than 1.5 mg, 1.25mg, or 1 mg of frovatriptan is administered to the mammal in any 2 hourperiod.

[0050] Typically, where the antimigraine compound is naratriptan, lessthan 0.8 mg of naratriptan is administered to the mammal in any 2 hourperiod. Preferably, less than 0.6 mg of naratriptan is administered tothe mammal in any 2 hour period. More preferably, less than 0.4 mg ofnaratriptan is inhaled by the mammal in any 2 hour period.

[0051] In a kit aspect of the present invention, a kit for deliveringsumatriptan, frovatriptan, or naratriptan through an inhalation route toa mammal is provided which comprises: a) a composition comprising atleast 5 percent by weight of sumatriptan, frovatriptan, or naratriptan;and, b) a device that forms a sumatriptan, frovatriptan, or naratriptanaerosol from the composition, for inhalation by the mammal. Preferably,the composition comprises at least 20 percent, 30 percent, 40 percent,50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent,97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of sumatriptan, frovatriptan, or naratriptan.

[0052] Typically, the device contained in the kit comprises: a) anelement for heating the sumatriptan, frovatriptan, or naratriptancomposition to form a vapor; b) an element allowing the vapor to cool toform an aerosol; and, c) an element permitting the mammal to inhale theaerosol.

[0053] Typically, where the kit comprises sumitriptan, it comprises lessthan 20 mg of sumitriptan. Preferably, the kit comprises less than 15 mgof sumitriptan. More preferably, it comprises less than 10 mg or 5 mg ofsumitriptan.

[0054] Typically, where the kit comprises frovatriptan, it comprisesless than 2 mg of frovatriptan. Preferably, the kit comprises less than1.75 mg of frovatriptan. More preferably, it comprises less than 1.5 mg,1.25 mg, or 1 mg of frovatriptan.

[0055] Typically, where the kit comprises naratriptan, it comprises lessthan 0.8 mg of naratriptan. Preferably, the kit comprises less than 0.6mg of naratriptan. More preferably, the kit comprises less than 0.4 mgof naratriptan.

BRIEF DESCRIPTION OF THE FIGURE

[0056]FIG. 1 shows a cross-sectional view of a device used to deliversumatriptan, frovatriptan, or naratriptan aerosols to a mammal throughan inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

[0057] Definitions

[0058] “Aerodynamic diameter” of a given particle refers to the diameterof a spherical droplet with a density of 1 g/mL (the density of water)that has the same settling velocity as the given particle.

[0059] “Aerosol” refers to a suspension of solid or liquid particles ina gas.

[0060] “Aerosol drug mass density” refers to the mass of sumatriptan,frovatriptan, or naratriptan per unit volume of aerosol.

[0061] “Aerosol mass density” refers to the mass of particulate matterper unit volume of aerosol.

[0062] “Aerosol particle density” refers to the number of particles perunit volume of aerosol.

[0063] “Amorphous particle” refers to a particle that does not containmore than 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent by weight of a crystalline form.

[0064] “Condensation aerosol” refers to an aerosol formed byvaporization of a substance followed by condensation of the substanceinto an aerosol.

[0065] “Frovatriptan” refers to3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole.

[0066] “Frovatriptan degradation product” refers to a compound resultingfrom a chemical modification of frovatriptan. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0067] “Inhalable aerosol drug mass density” refers to the aerosol drugmass density produced by an inhalation device and delivered into atypical patient tidal volume.

[0068] “Inhalable aerosol mass density” refers to the aerosol massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

[0069] “Inhalable aerosol particle density” refers to the aerosolparticle density of particles of size between 100 nm and 5 micronsproduced by an inhalation device and delivered into a typical patienttidal volume.

[0070] “Naratriptan” refers toN-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethane-sulfonamide.

[0071] “Naratriptan degradation product” refers to a compound resultingfrom a chemical modification of naratriptan. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0072] “Mass median aerodynamic diameter” or “MMAD” of an aerosol refersto the aerodynamic diameter for which half the particulate mass of theaerosol is contributed by particles with an aerodynamic diameter largerthan the MMAD and half by particles with an aerodynamic diameter smallerthan the MMAD.

[0073] “Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

[0074] “Rate of inhalable aerosol particle formation” refers to thenumber of particles of size between 100 nm and 5 microns produced by aninhalation device per unit time.

[0075] “Rate of drug aerosol formation” refers to the mass ofaerosolized sumatriptan, frovatriptan, or naratriptan produced by aninhalation device per unit time.

[0076] “Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

[0077] “Sumatriptan” refers to3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide.

[0078] “Sumatriptan degradation product” refers to a compound resultingfrom a chemical modification of sumatriptan. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0079] “Typical patient tidal volume” refers to 1 L for an adult patientand 15 mL/kg for a pediatric patient.

[0080] “Vapor” refers to a gas, and “vapor phase” refers to a gas phase.The term “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

[0081] Formation of Sumatriptan, Frovatriptan, or Naratriptan ContainingAerosols

[0082] Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising sumatriptan, frovatriptan, or naratriptan to form a vapor,followed by cooling of the vapor such that it condenses to provide asumatriptan, frovatriptan, or naratriptan comprising aerosol(condensation aerosol). The composition is heated in one of four forms:as pure active compound (i.e., pure sumatriptan, frovatriptan, ornaratriptan); as a mixture of active compound and a pharmaceuticallyacceptable excipient; as a salt form of the pure active compound; and,as a mixture of active compound salt form and a pharmaceuticallyacceptable excipient.

[0083] Salt forms of sumatriptan, frovatriptan, or naratriptan areeither commercially available or are obtained from the correspondingfree base using well known methods in the art. A variety ofpharmaceutically acceptable salts are suitable for aerosolization. Suchsalts include, without limitation, the following: hydrochloric acid,hydrobromic acid, acetic acid, maleic acid, formic acid, and fumaricacid salts.

[0084] Pharmaceutically acceptable excipients may be volatile ornonvolatile. Volatile excipients, when heated, are concurrentlyvolatilized, aerosolized and inhaled with sumatriptan, frovatriptan, ornaratriptan. Classes of such excipients are known in the art andinclude, without limitation, gaseous, supercritical fluid, liquid andsolid solvents. The following is a list of exemplary carriers within theclasses: water; terpenes, such as menthol; alcohols, such as ethanol,propylene glycol, glycerol and other similar alcohols;dimethylformamide; dimethylacetamide; wax; supercritical carbon dioxide;dry ice; and mixtures thereof.

[0085] Solid supports on which the composition is heated are of avariety of shapes. Examples of such shapes include, without limitation,cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mmthickness and virtually any shape permeated by small (e.g., less than1.0 mm-sized) pores. Preferably, solid supports provide a large surfaceto volume ratio (e.g., greater than 100 per meter) and a large surfaceto mass ratio (e.g., greater than 1 cm² per gram).

[0086] A solid support of one shape can also be transformed into anothershape with different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

[0087] A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yams and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

[0088] Where aluminum is used as a solid support, aluminum foil is asuitable material. Examples of silica, alumina and silicon basedmaterials include amphorous silica S-5631 (Sigma, St. Louis, Mo.),BCR171 (an alumina of defined surface area greater than 2 m²/g fromAldrich, St. Louis, Mo.) and a silicon wafer as used in thesemiconductor industry. Carbon yams and felts are available fromAmerican Kynol, Inc., New York, N.Y. Chromatography resins such asoctadecycl silane chemically bonded to porous silica are exemplarycoated variants of silica.

[0089] The heating of the sumatriptan, frovatriptan, or naratriptancompositions is performed using any suitable method. Examples of methodsby which heat can be generated include the following: passage of currentthrough an electrical resistance element; absorption of electromagneticradiation, such as microwave or laser light; and, exothermic chemicalreactions, such as exothermic salvation, hydration of pyrophoricmaterials and oxidation of combustible materials.

[0090] Delivery of Sumatriptan, Frovatriptan, or Naratriptan ContainingAerosols

[0091] Sumatriptan, frovatriptan, or naratriptan containing aerosols ofthe present invention are delivered to a mammal using an inhalationdevice. Where the aerosol is a sumatriptan, frovatriptan, or naratriptancontaining composition to form a vapor; an element allowing the vapor tocool, thereby providing a condensation aerosol; and, an elementpermitting the mammal to inhale the aerosol. Various suitable heatingmethods are described above. The element that allows cooling is, in itsimplest form, an inert passageway linking the heating means to theinhalation means. The element permitting inhalation is an aerosol exitportal that forms a connection between the cooling element and themammal's respiratory system.

[0092] One device used to deliver the sumatriptan, frovatriptan, ornaratriptan containing aerosol is described in reference to FIG. 1.Delivery device 100 has a proximal end 102 and a distal end 104, aheating module 106, a power source 108, and a mouthpiece 110. Asumatriptan, frovatriptan, or naratriptan composition is deposited on asurface 112 of heating module 106. Upon activation of a user activatedswitch 114, power source 108 initiates heating of heating module 106(e.g, through ignition of combustible fuel or passage of current througha resistive heating element). The sumatriptan, frovatriptan, ornaratriptan composition volatilizes due to the heating of heating module106 and condenses to form a condensation aerosol prior to reaching themouthpiece 110 at the proximal end of the device 102. Air flow travelingfrom the device distal end 104 to the mouthpiece 110 carries thecondensation aerosol to the mouthpiece 110, where it is inhaled by themammal.

[0093] Devices, if desired, contain a variety of components tofacilitate the delivery of sumatriptan, frovatriptan, or naratriptancontaining aerosols. For instance, the device may include any componentknown in the art to control the timing of drug aerosolization relativeto inhalation (e.g., breath-actuation), to provide feedback to patientson the rate and/or volume of inhalation, to prevent excessive use (i.e.,“lock-out” feature), to prevent use by unauthorized individuals, and/orto record dosing histories.

[0094] Dosage of Sumatriptan, Frovatriptan, or Naratriptan ContainingAerosols

[0095] Sumatriptan, frovatriptan, and naratriptan are given at strengthsof 25 mg, 2.5 mg, and 1 mg respectively for the treatment of migraineheadaches. As aerosols, 5 mg to 40 mg of sumatriptan, 0.5 mg to 4 mg offrovatriptan, and 0.2 mg to 2 mg naratriptan are generally provided forthe same indication. A typical dosage of a sumatriptan, frovatriptan, ornaratriptan aerosol is either administered as a single inhalation or asa series of inhalations taken within an hour or less (dosage equals sumof inhaled amounts). Where the drug is administered as a series ofinhalations, a different amount may be delivered in each inhalation. Thedosage amount of sumatriptan, frovatriptan, or naratriptan in aerosolform is generally no greater than twice the standard dose of the druggiven orally.

[0096] One can determine the appropriate dose of sumatriptan,frovatriptan, or naratriptan containing aerosols to treat a particularcondition using methods such as animal experiments and a dose-finding(Phase I/II) clinical trial. One animal experiment involves measuringplasma concentrations of drug in an animal after its exposure to theaerosol. Mammals such as dogs or primates are typically used in suchstudies, since their respiratory systems are similar to that of a human.Initial dose levels for testing in humans is generally less than orequal to the dose in the mammal model that resulted in plasma druglevels associated with a therapeutic effect in humans. Dose escalationin humans is then performed, until either an optimal therapeuticresponse is obtained or a dose-limiting toxicity is encountered.

[0097] Analysis of Sumatriptan, Frovatriptan, or Naratriptan ContainingAerosols

[0098] Purity of a sumatriptan, frovatriptan, or naratriptan containingaerosol is determined using a number of methods, examples of which aredescribed in Sekine et al., Journal of Forensic Science 32:1271-1280(1987) and Martin et al., Journal of Analytic Toxicology 13:158-162(1989). One method involves forming the aerosol in a device throughwhich a gas flow (e.g., air flow) is maintained, generally at a ratebetween 0.4 and 60 L/min. The gas flow carries the aerosol into one ormore traps. After isolation from the trap, the aerosol is subjected toan analytical technique, such as gas or liquid chromatography, thatpermits a determination of composition purity.

[0099] A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

[0100] The gas or liquid chromatograph discussed above contains adetection system (i.e., detector). Such detection systems are well knownin the art and include, for example, flame ionization, photon absorptionand mass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure ofsumatriptan, frovatriptan, or naratriptan degradation products.

[0101] Particle size distribution of a sumatriptan, frovatriptan, ornaratriptan containing aerosol is determined using any suitable methodin the art (e.g., cascade impaction). An Andersen Eight Stage Non-viableCascade Impactor (Andersen Instruments, Smyrna, Ga.) linked to a furnacetube by a mock throat (USP throat, Andersen Instruments, Smyrna, Ga.) isone system used for cascade impaction studies.

[0102] Inhalable aerosol mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the mass collected in the chamber.Typically, the aerosol is drawn into the chamber by having a pressuregradient between the device and the chamber, wherein the chamber is atlower pressure than the device. The volume of the chamber shouldapproximate the tidal volume of an inhaling patient.

[0103] Inhalable aerosol drug mass density is determined, for example,by delivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

[0104] Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size is determined bymeasuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*ω/6, whereD is a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, (p is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

[0105] Rate of inhalable aerosol particle formation is determined, forexample, by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

[0106] Rate of aerosol formation is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice. The delivery is for a set period of time (e.g., 3 s), and themass of particulate matter collected is determined by weighing theconfined chamber before and after the delivery of the particulatematter. The rate of aerosol formation is equal to the increase in massin the chamber divided by the duration of the collection time.Alternatively, where a change in mass of the delivery device orcomponent thereof can only occur through release of the aerosol phaseparticulate matter, the mass of particulate matter may be equated withthe mass lost from the device or component during the delivery of theaerosol. In this case, the rate of aerosol formation is equal to thedecrease in mass of the device or component during the delivery eventdivided by the duration of the delivery event.

[0107] Rate of drug aerosol formation is determined, for example, bydelivering a sumatriptan, frovatriptan, or naratriptan containingaerosol into a confined chamber via an inhalation device over a setperiod of time (e.g., 3 s). Where the aerosol is pure sumatriptan,frovatriptan, or naratriptan, the amount of drug collected in thechamber is measured as described above. The rate of drug aerosolformation is equal to the amount of sumatriptan, frovatriptan, ornaratriptan collected in the chamber divided by the duration of thecollection time. Where the sumatriptan, frovatriptan, or naratriptancontaining aerosol comprises a pharmaceutically acceptable excipient,multiplying the rate of aerosol formation by the percentage ofsumatriptan, frovatriptan, or naratriptan in the aerosol provides therate of drug aerosol formation.

[0108] Utility of Sumatriptan, Frovatriptan, or Naratriptan ContainingAerosols

[0109] The sumatriptan, frovatriptan, or naratriptan containing aerosolsof the present invention are typically used for the treatment ofmigraine headaches.

[0110] The following examples are meant to illustrate, rather thanlimit, the present invention.

[0111] Sumatriptan, frovatriptan and naratriptan are commerciallyavailable as the active ingredients in tablets sold asIMITREX®(sumitriptan), FROVA®(frovatriptan succinate), and AMERGE®(naratriptan hydrochloride) respectively.

EXAMPLE 1 General Procedure for Obtaining Free Base of a Compound Salt

[0112] Approximately 1 g of salt (e.g., mono hydrochloride) is dissolvedin deionized water (˜30 mL). Three equivalents of sodium hydroxide (1 NNaOH_(aq)) is added dropwise to the solution, and the pH is checked toensure it is basic. The aqueous solution is extracted four times withdichloromethane (˜50 mL), and the extracts are combined, dried (Na₂SO₄)and filtered. The filtered organic solution is concentrated using arotary evaporator to provide the desired free base. If necessary,purification of the free base is performed using standard methods suchas chromatography or recrystallization.

EXAMPLE 2 General Procedure for Volatilizing Compounds from Halogen Bulb

[0113] A solution of drug in approximately 120 μL dichloromethane iscoated on a 3.5 cm×7.5 cm piece of aluminum foil (precleaned withacetone). The dichloromethane is allowed to evaporate. The coated foilis wrapped around a 300 watt halogen tube (Feit Electric Company, PicoRivera, Calif.), which is inserted into a glass tube sealed at one endwith a rubber stopper. Running 118 V of alternating current (driven byline power controlled by a variac) through the bulb for 2.2 s affordsthermal vapor (including aerosol), which is collected on the glass tubewalls. Reverse-phase HPLC analysis with detection by absorption of 225nm light is used to determine the purity of the aerosol. (When desired,the system is flushed through with argon prior to volatilization.)

[0114] The following aerosols were obtained using this procedure:sumatriptan aerosol (˜0.56 mg, 97.2% purity); frovatriptan aerosol (0.39mg, 94.8 % purity); and, naratriptan aerosol (0.58 mg, 96.2% purity). Toobtain higher purity aerosols, one can coat a lesser amount of drug,yielding a thinner film to heat. A linear decrease in film thickness isassociated with a linear decrease in impurities.

EXAMPLE 3 Particle Size, Particle Density, and Rate of InhalableParticle Formation of Frovatriptan Aerosol

[0115] A solution of 5.0 mg frovatriptan in 100 μL methanol was spreadout in a thin layer on the central portion of a 3.5 cm×7 cm sheet ofaluminum foil. The methanol was allowed to evaporate. The aluminum foilwas wrapped around a 300 watt halogen tube, which was inserted into aT-shaped glass tube. Both of the openings of the tube were left open andthe third opening was connected to a 1 liter, 3-neck glass flask. Theglass flask was further connected to a large piston capable of drawing1.1 liters of air through the flask. Alternating current was run throughthe halogen bulb by application of 90 V using a variac connected to 110V line power. Within 1 s, an aerosol appeared and was drawn into the 1 Lflask by use of the piston, with collection of the aerosol terminatedafter 6 s. The aerosol was analyzed by connecting the 1 L flask to aneight-stage Andersen non-viable cascade impactor. Results are shown intable 1. MMAD of the collected aerosol was 1.8 microns with a geometricstandard deviation of 2.1. Also shown in table 1 is the number ofparticles collected on the various stages of the cascade impactor, givenby the mass collected on the stage divided by the mass of a typicalparticle trapped on that stage. The mass of a single particle ofdiameter D is given by the volume of the particle, πD³/6, multiplied bythe density of the drug (taken to be 1 g/cm³). The inhalable aerosolparticle density is the sum of the numbers of particles collected onimpactor stages 3 to 8 divided by the collection volume of 1 L, givingan inhalable aerosol particle density of 7.3×10⁵ particles/mL. The rateof inhalable aerosol particle formation is the sum of the numbers ofparticles collected on impactor stages 3 through 8 divided by theformation time of 6 s, giving a rate of inhalable aerosol particleformation of 1.2×10⁸ particles/second.

[0116] Table 1: Determination of the characteristics of a frovatriptancondensation aerosol by cascade impaction using an Andersen 8-stagenon-viable cascade impactor run at 1 cubic foot per minute air flow.Mass Particle size Average particle collected Number of Stage range(microns) size (microns) (mg) particles 0 9.0-10.0 9.5 0.01 1.3 × 10⁴ 15.8-9.0 7.4 0.02 8.0 × 10⁴ 2 4.7-5.8 5.25 0.03 3.8 × 10⁵ 3 3.3-4.7 4.00.05 1.6 × 10⁶ 4 2.1-3.3 2.7 0.09 9.1 × 10⁶ 5 1.1-2.1 1.6 0.16 7.6 × 10⁷6 0.7-1.1 0.9 0.09 2.4 × 10⁸ 7 0.4-0.7 0.55 0.04 4.0 × 10⁸ 8   0-0.4 0.20.0 0

EXAMPLE 4 Drug Mass Density and Rate of Drug Aerosol Formation ofFrovatriptan Aerosol

[0117] A solution of 5.0 mg frovatriptan in 100 μL methanol was spreadout in a thin layer on the central portion of a 3.5 cm×7 cm sheet ofaluminum foil. The methanol was allowed to evaporate. The aluminum foilwas wrapped around a 300 watt halogen tube, which was inserted into aT-shaped glass tube. Both of the openings of the tube were left open andthe third opening was connected to a 1 liter, 3-neck glass flask. Theglass flask was further connected to a large piston capable of drawing1.1 liters of air through the flask. Alternating current was run throughthe halogen bulb by application of 90 V using a variac connected to 110V line power. Within seconds, an aerosol appeared and was drawn into the1 L flask by use of the piston, with formation of the aerosol terminatedafter 6 s. The aerosol was allowed to sediment onto the walls of the 1 Lflask for approximately 30 minutes. The flask was then extracted withacetonitrile and the extract analyzed by HPLC with detection by lightabsorption at 225 nm. Comparison with standards containing known amountsof frovatriptan revealed that 0.85 mg of >91% pure frovatriptan had beencollected in the flask, resulting in an aerosol drug mass density of0.85 mg/L. The aluminum foil upon which the frovatriptan had previouslybeen coated was weighed following the experiment. Of the 5.0 mgoriginally coated on the aluminum, 2.8 mg of the material was found tohave aerosolized in the 6 s time period, implying a rate of drug aerosolformation of 0.5 mg/s.

EXAMPLE 5 Flash Device for Forming Aerosols

[0118] A high-power flashcube (GE or Sylvania), which can produce300-400 J of energy, was inserted into an anodized aluminum tube. Theflashcube/tube assembly was dipped into an organic solution containing adrug and quickly removed. Evaporation of residual solvent from theassembly was performed by placing it into a vacuum chamber for 30 min.This left a film of drug coated on the exterior surface of the aluminumtube. The flashbulb assembly was electrically connected to two 1.5 Vbatteries and a switch using copper wires and then enclosed in a sealed,glass vial. Ignition of the flashbulb was performed by momentarilyturning on the switch between the flashbulb and batteries. Afterignition, the vial was kept closed for 30 minutes such that particles ofvolatilized drug coagulated and condensed on the inside surface of thevial. Analysis of the aerosol involved rinsing the vial with 5 mL ofacetonitrile and injecting a sample of the organic solution into anHPLC. Frovatriptan (0.45 mg) aerosol was obtained in approximately 92%purity using this procedure.

1. A method of treating migraine comprising administering a therapeuticamount of a sumatriptan, frovatriptan or naratriptan condensationaerosol, having an MMAD less than 3 μm and less than 5% sumatriptan,frovatriptan or naratriptan degradation products, to a patient byinhalation, upon activation by the patient of the formation of, anddelivery of, the condensation aerosol.
 2. The method of claim 1, whereinsaid condensation aerosol is formed by a. volatilizing sumatriptan,frovatriptan or naratriptan under conditions effective to produce aheated vapor of the sumatriptan, frovatriptan or naratriptan, and b.condensing the heated vapor of the sumatriptan, frovatriptan ornaratriptan to form condensation aerosol particles.
 3. The methodaccording to claim 1, wherein the condensation aerosol is formed at arate greater than 0.5 mg/second.
 4. The method according to claim 1,wherein said therapeutic amount of sumatriptan condensation aerosolcomprises between 5 mg and 40 mg of sumatriptan delivered in a singleinspiration.
 5. The method according to claim 1, wherein saidtherapeutic amount of frovatriptan condensation aerosol comprisesbetween 0.5 mg and 4 mg of frovatriptan delivered in a singleinspiration.
 6. The method according to claim 1, wherein saidtherapeutic amount of naratriptan condensation aerosol comprises between0.2 mg and 2 mg of naratriptan delivered in a single inspiration.
 7. Themethod according to claim 2, wherein said administration results in apeak plasma concentration of said sumatriptan, frovatriptan ornaratriptan in less than 0.1 hours.
 8. The method according to claim 1,wherein at least 50% by weight of the condensation aerosol is amorphousin form.
 9. A method of administering sumatriptan, frovatriptan ornaratriptan to a patient to achieve a peak plasma drug concentrationrapidly, comprising administering to the patient by inhalation anaerosol of sumatriptan, frovatriptan or naratriptan having less than 5%sumatriptan, frovatriptan or naratriptan degradation products and anMMAD less than 3 microns wherein the peak plasma drug concentration isachieved in less than 0.1 hours.
 10. A kit for delivering a drug aerosolcomprising: a) a thin coating of a sumatriptan, frovatriptan ornaratriptan composition, and b) a device for dispensing said thincoating as a condensation aerosol.
 11. The kit of claim 10, wherein thedevice for dispensing said coating as a condensation aerosol comprises:(a) a flow through enclosure, (b) contained within the enclosure, ametal substrate with a foil-like surface and having a thin coating ofsumatriptan, frovatriptan or naratriptan composition formed on thesubstrate surface, (c) a power source that can be activated to heat thesubstrate to a temperature effective to volatilize the sumatriptan,frovatriptan or naratriptan composition contained in said coating, and(d) inlet and exit portals through which air can be drawn through saiddevice by inhalation, wherein heating the substrate by activation of thepower source is effective to form a sumatriptan, frovatriptan ornaratriptan vapor containing less than 5% sumatriptan, frovatriptan ornaratriptan degradation products, and drawing air through said chamberis effective to condense the sumatriptan, frovatriptan or naratriptanvapor to form aerosol particles wherein the aerosol has an MMAD of lessthan 3 microns.
 12. The kit according to claim 11, wherein the heat forheating the substrate is generated by an exothermic chemical reaction.13. The kit according to claim 12, wherein said exothermic chemicalreaction is oxidation of combustible materials.
 14. The kit according toclaim 11, wherein the heat for heating the substrate is generated bypassage of current through an electrical resistance element.
 15. The kitaccording to claim 11, wherein said substrate has a surface areadimensioned to accommodate a therapeutic dose of sumatriptan,frovatriptan or naratriptan composition in said coating.
 16. The kitaccording to claim 10, wherein a peak plasma concentration ofsumatriptan, frovatriptan or naratriptan is obtained in less than 0.1hours after delivery of condensation aerosol to the pulmonary system.17. The kit of claim 10, further including instructions for use.